Gatifloxacin, chemically 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl piperazin-1-yl)-4-oxo-1,4-dihydro-3-quinoline carboxylic acid, is represented by the following formula,

Gatifloxacin belongs to the class of fluoroquinolones, has potent antibacterial activity, has higher selectivity against bacteria from mammalian cells, which results in excellent selective toxicity and is marketed under brand name “Tequin”. Gatifloxacin is preferably administered orally or intravenously and the usual dose is 400 mg once daily.
U.S. Pat. No. 4,980,470 describes the method for preparation of Gatifloxacin hemihydrate by condensation of 1-Cyclopropyl-6,7-fluoro-8-methoxy-1,4-dihydro-3-quinoline carboxylic acid with 2-methylpiperazine in anhydrous DMSO followed by column chromatographic purification and recrystallization from methanol.
European Patent No 464,823 discloses a method for the preparation of Gatifloxacin by condensation of 2-methyl piperazine with (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O3,O4)bis(acetate-O)-borate in presence of triethyl amine, acetonitrile followed by hydrolysis of the resulting intermediate [1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O3,O4]bis(acetate-O)-borate with triethyl amine in mixture of ethanol, water and crystallization from ethanol.
U.S. Pat. No. 5,880,283 describes the process for Gatifloxacin sesquihydrate by heating the aqueous suspension of 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl piperazin-1-yl)-4-oxo-1,4-dihydro-3-quinoline carboxylic acid to 80-90° C. followed by hot filtration at that temperature and drying.
U.S. Pat. No. 4,997,943 discloses the Gatifloxacin hydrochloride salts, describes the process for preparation of Gatifloxacin hydrochloride by reaction of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid boron difluoride chelate with 2-methyl piperazine in DMSO, isolating the intermediate 1-Cyclopropyl-7-(3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid boron difluoride chelate which on treatment with triethylamine in aqueous ethanol followed by isolation of the crystals and treating with hydrochloric acid in ethanol.
U.S. Pat. No. 6,413,969 discloses the several polymorphs or hydrate forms of Gatifloxacin and their X-ray diffraction patterns. The Sesquihydrate, pentahydrate and hexahydrate are crystallized directly from aqueous solutions. Other crystalline forms are crystallized from molten phase or by solid-solid transformations. U.S. Pat. No. 6,413,969 further describes Gatifloxacin pentahydrate as the most physically stable form and discloses the process for preparation of Gatifloxacin pentahydrate by water equilibration of any other crystal form of Gatifloxacin.
PCT Publication No WO 03/086402 discloses two anhydrous crystalline forms, Form-I and Form-II of Gatifloxacin, their X-ray diffraction pattern, DSC and IR spectrums and describes the methods for preparation as by removal of water azeotropically from Gatifloxacin hydrate in aromatic or aliphatic hydrocarbon. It further describes the Gatifloxacin hydrate used is having the moisture content ranging from 2.5 to 50.0%.
PCT Publication No. WO 03/94919 discloses the several crystalline forms of Gatifloxacin, Form-A, B, C, D, E1, F, G, H, J and their X-ray diffraction patterns, TGA, DSC and IR spectrums. This PCT publication further describes the process for the preparation methods for the crystalline forms Form-A to Form-J, Form-Ω and Form-T2RP by slurring/crystallization from iso-propanol (Form-A), n-butanol, ethanol (Form-B), n-butanol (Form-C), methanol (Form-D), aqueous methanol (Form-F, Form-G), toluene (Form-H), n-butanol (Form-I, without drying) and the solvated forms Form-J with isopropanol, methyl ethyl ketone, acetone, n-butanol and THF. The Form-E1 is prepared from the mixture of acetonitrile-water, preparation methods for Form-Ω and Form-T2RP were also disclosed.
PCT Publication No WO 03/105851 discloses Gatifloxacin crystalline forms Form-O, mixture of Form-O Sesquihydrate, Form-V and the methods for making them. The Form-O contains the water content equivalent to trihydrate (11.8%), prepared by crystallization from mixed solvent of ethanol-acetonitrile and is the wet compound. The Form-V having the water content about 1% to 3% is prepared by crystallization and treating the isolated solid with moist gas.
PCT Publication No WO 04/12739 discloses the several crystalline forms of Gatifloxacin, Form-L, Form-M, Form-P, Form-Q, Form-S and Form-T1 along with their preparation methods as follows. The Form-L by recrystallization from methanol:water (90:10), Form-M by slurrying in absolute ethanol, Form-P by recrystallization from ethanol:water (99:1), Form-Q by recrystallization from acetonitrile:water (98:2), Form-S by recrystallization of wet Gatifloxacin from acetonitrile followed by slurrying in ethanol resulted the wet compound. After drying this Form-S becomes the Form-T2RP. The dry Gatifloxacin on recrystallization from acetonitrile, followed by slurrying in ethanol and drying under vacuum gives the Form-T1.
Our co-pending Indian patent application No. 603/CHE/2003 discloses the preparation of Gatifloxacin by reaction of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with aq. hydrofluoroboricacid followed by Isolation of the intermediate, condensation with 2-methyl piperazine, hydrolysis of the resulted intermediate 1-cyclopropyl-7-(3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-oxo-1,4-dihydro-3-quinoline carboxylic acid boron difluoride chelate with triethyl amine in 20% aqueous ethanol and recrystallization from methanol as Gatifloxacin hemihydrate. The X-ray diffraction pattern, IR spectrum of the obtained Gatifloxacin hemihydrate also disclosed.
Surprisingly it has been observed that when recrystallization of Gatifloxacin is attempted in various solvents, new crystalline forms of Gatifloxacin having the water content about 2-5%, characterized by their unique x-ray diffraction pattern.